Pharmacology of the Autonomic Nervous System (ANS) Flashcards
ANS subdivisions
- Sympathetic (thoracolumbar, fight or flight)
- Parasympathetic (craniosacral, rest and digest)
β1 on heart sinoatrial node
Increase in heart rate
M2 in heart sinoatrial node
Decrease in heart rate
β1 in heart atria
Increase in contractility and conduction velocity
M2 in heart atria
Decrease in contractility
β2 in lungs (tracheal and bronchial)
Relaxation
M2=M3 in lungs (bronchial and trachial)
Contraction
α1 in Eye (radial muscle “iris”)
Contraction (mydriasis)
M3, M2 in sphincter muscle (iris)
Contraction (miosis)
β2 in ciliary muscle of eye
M3, M2 for ciliary muscle of eyes
Contraction for near vision
Parasympathetic
Neurotransmitters: ACh
Receptors: nAChR, mAChR
Sympathetic
Neurotransmitters: NE > Epi (DA); ACh
Receptors: α, β, (D), nAChR, mAChR
Acetylcholine (cholinergic)
- The major neurotransmitter of the parasympathetic nervous system
- All preganglionic autonomic fibers
- All postganglionic parasympathetic fibers
- Few postganglionic sympathetic fibers (sweat glands)
Norepinephrine (adrenergic)
- The major neurotransmitter of the sympathetic nervous system
- The vast majority of postganglionic sympathetic fibers
Epinephrine (adrenergic)
•Synthesis only occurs in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem
Dopamine (dopaminergic)
- NE and Epi precursor
- Acts on the CNS and renal vascular smooth muscle
Co-neurotransmitters
ATP, neuropeptide Y, vasoactive intestinal peptide, substance P, others
Junctional transmission
1) Synthesis of acetylcholine (ACh)
2) Storage
3) Release
4) Destruction
nAChR (ionotropic)
Ion channels (fast) -Acetylcholine (Nicotine)
CNS
Autonomic ganglia (NN)
-Excitatory
Adrenal medula (NN)
-Release of
catecholamines
mAChR (metabotropic)
G Protein coupled receptor - Acetylcholine (Muscarine)
CNS
Autonomic ganglia
Effector organs (cardiac and
smooth muscle, gland cells,
nerve terminals)
Sweat glands
Sweat secretion
M2 on Heart, nerves, smooth muscle
GPCR, Gi/o
Inhibition of adenylyl cyclase (AC); ↓cAMP production, activation of K+
channels
M3 on Glands, smooth muscle, endothelium
GPCR, **Gq/11 **
Activation of PLC; IP3, DAG cascade
Junctional transmission
Adrenergic nerve terminal
1) Synthesis
2) Storage
3) Release
4) Reuptake
Termination of catecholamine signaling
Reuptake into nerve terminals
- Major mechanism that terminates the actions of catecholamines
- NET (norepinephrine transporter) and DAT (dopamine transporter)
- After reuptake, catecholamines are stored in vesicles by the VMAT-2
Metabolism of catecholamines (2 main enzymes)
•Monoamine oxidase (MAO)
•Catechol-O-methyltransferase (COMT)
\*In contrast to cholinergic signaling, termination of catecholamine action by degradative enzymes (i.e., AChE) is nonexistent in adrenergic signaling
α-receptors
- GPCR
- Pre- and postjunctional
- Two major subtypes (α1,α2)
β-receptors
- GPCR
- Pre- and postjunctional
- Three major subtypes (β1, β2, β3)
Adrenergic signaling
Na+-dependent tyrosine transporter
•Transports tyrosine into the nerve terminal
Vesicular monoamine transporter (VMAT-2)
•Transports NE, Epi, DA, and serotonin into vesicles (promiscuous)
Release upon action potential and Ca2+ influx
NE transporter (NET)
_*Cocaine inhibits this giving sympathetic effects_
•Imports NE into the nerve terminal
•DAT imports DA into the nerve terminal
Alpha1 adrenergic receptor
Gq
↑phospholipase C, IP3 and DAG, intracellular Ca2+
Epi ≥ NE >> Isoproterenol
Phenylephrine
smooth muscle - contraction
Intestinal smooth muscle - hyperpolarization and relaxation
Heart - Increased contractile force; arrhythmias
Alpha2 adrenergic receptor
Gi, Go
↓adenylyl cyclase
↓cAMP
Epi ≥ NE >> Iso
Clonidine
Vascular smooth muscle
Contraction
Beta1 adrenergic receptor
Gs
↑adenylyl cyclase, cAMP, Ltype
Ca2+ channel opening
Iso > Epi = NE
Dobutamine
Juxtaglomerular cells
Increased renin secretion
Heart
Increased force and rate of contraction and
AV nodal conduction velocity
Beta2 adrenergic receptor
Gs
↑adenylyl cyclase, cAMP, Ltype
Ca2+ channel opening
Iso > Epi >> NE
Terbutamine
Smooth muscle (vascular, bronchial, GI, GU)
Relaxation
Beta3 adrenergic receptor
Gs
↑adenylyl cyclase, cAMP, Ltype
Ca2+ channel opening
Iso = NE > Epi
Adipose tissue
Lipolysis
Sympathomimetic agents: drugs that mimic or enhance α-and β-receptor stimulation
Epinephrine (α1 = α2, β1 = β2)
Norepinephrine (α1 = α2, β1 >> β2)
Isoproterenol (β1 = β2 >>>> α)
Primary Tissue Locations of Adrenergic Receptor Subtypes
Rules of thumb for smooth muscle and autonomic receptors
Alpha-1 (α1) receptors
•Stimulate contraction of all smooth muscle
•Vascular smooth muscle – vasoconstriction
Beta-2 (β2) receptors
•Relax smooth muscle – vasodilation
Muscarinic receptors
•Contract smooth muscle (different intracellular signal than α1 receptors)
(Depends on relative receptor density.)
Response of blood vessels to autonomic
nerve impulses
•Blood vessels are innervated by adrenergic receptors, which cause vessel
constriction when activated (sympathetic)
- Smooth muscle of blood vessels is NOT innervated by parasympathetic neurons
- Neither mAChRs nor nAChRs are found on smooth muscle of blood vessels
•Blood vessels relax in response to parasympathetic release of ACh as long as the
epithelium is intact
•Apparent discrepancy – ACh & muscarinic agonists given IV cause vasodilation due to
release of nitric oxide (NO)
mAChRs, EDRF (NO), and vessel relaxation
Activation of mAChRs on epithelial cells causes production and release of
endothelium-derived relaxing factor (EDRF), also known as nitric oxide (NO)
Stimulation of NO release can occur from ACh, vasoactive
products, and physical stimuli.
Nitroglycerin is similar to the NO as it
helps open up the smooth
muscle vessels.
Adrenal medulla
•Sympathetic innervation
- Epi and NE release is triggered by the release of ACh from the preganglionic fibers
- ACh binds to NNAChRs (on chromaffin cells) and produce a localized depolarization
•Release is approximately:
80% Epi
20% NE
Baroreceptor reflex as an
example of compensatory
changes in the ANS
Balance between sympathetic and
parasympathetic. When we’re laying down
and everything is vasodilated. Blood
pressure is low when relaxing. When we get
up the blood pressure goes up.
